Differential Role of p38 in IL-1α Induction of MMP-9 and MMP-13 in an Established Liver Myofibroblast Cell Line

Interleukin-1 (IL-1) has been implicated in the regulation of the expression of various matrix metalloproteinases (MMPs) in many mesenchymal cell types, but its role in liver myofibroblasts (MFs) has not been elucidated. A myofibroblast-like cell line, MG2, was derived from an isolate of rat hepatic stellate cells (HSCs). These cells expressed desmin, vimentin, smooth muscle alpha-actin, and fibulin-2. Using a recombinant IL-1alpha at 5 ng/ml, it was shown that IL-1alpha would upregulate, while IL-1Ra, an IL-1 receptor antagonist, would down-regulate the expression of IL-1alpha mRNA in MG2 cells, indicating the presence of an autostimulatory loop of IL-1alpha in these cells. Besides, a paracrine source of IL-1 may be produced from Kupffer cells, as we showed primarily cultured Kupffer cells responded much more remarkably than MG2 cells to lipopolysaccharide stimuli to produce both IL-1alpha and IL-1beta. Recombinant IL-1alpha upregulated the expression of both MMP-9 and -13, and the induction of MMP-13 but not MMP-9 could be inhibited by SB203580, an inhibitor of p38. Similarly, in primarily cultured human liver MFs, upregulation of MMP-1 by IL-1alpha was also shown to be inhibited by SB203580. All of these data suggested that, during liver inflammation, IL-1 produced by an autocrine model from MFs or by a paracrine model from Kupffer cells might play a crucial role in the remodeling of liver fibrosis through an either p38-dependent or p38-independent pathway to regulate the expression of various MMPs by liver MFs.